1. Field of the Invention
The present invention relates to treatments for increasing muscle mass. More specifically, the present invention relates to treatments for wasting and lipodystrophy including, but not limited to, in HIV-infected individuals. The present invention also relates to treatments for increasing CD4+ lymphocyte levels, particularly in HIV-infected individuals.
2. Description of Related Art
a. HIV
Infection with the HIV virus and the subsequent disease known as AIDS manifests itself clinically in a loss of CD4+ T lymphocytes that are targets of the virus. HIV-positive patients monitor their disease through periodic assessment of CD4+ lymphocyte counts or the CD4+/CD8+ lymphocyte ratio and use these measurements for making a decision when to begin AIDS therapies or how to tailor the therapies. Men with AIDS often face not only the wasting and debilitating effects of opportunistic microbiological infections typical of AIDS, but also a loss of muscle mass as part of a condition known as lipodystrophy. In addition to muscle mass loss, lipodystrophy is characterized by a build-up of fat in certain body areas, a loss of fat in certain body areas, high levels of triglycerides and cholesterol in the blood, and high levels of blood glucose and insulin. The condition is aggravated or may be caused directly by drug cocktails used to treat AIDS. Current treatments for symptoms associated with lipodystrophy include plastic surgery such as liposuction, diet and exercises, lipid-lowering drugs and anabolic drugs.
Men and women present lipodystrophy differently, consequently, sex hormones may play a role in onset of the disease. In support of this observation, many HIV-positive men experience significant endocrine problems such as decreased production of IGF and testosterone. Hypogonadism is a common problem in HIV-infected men with rates from 25% to 45%, depending on the stage of AIDS disease. Possible causes of hypogonadism include infections of the testicles (including with HIV), drug side effects (including side effects from ketoconazole, ganciclovir, and megestrol acetate) and elevated cortisol.
b. Testosterone Therapy
Testosterone therapy is being used in up to 80% of the HIV-infected men with a loss of muscle mass. Testosterone is the primary male androgen, playing a vital role in overall male health. Testosterone is essential to the development and maintenance of specific reproductive tissues (testes, prostate, epididymis, seminal vesicle, and penis) and male secondary sex characteristics. It plays a key role in libido and erectile function and is necessary for the initiation and maintenance of spermatogenesis. Testosterone also has important functions not related to reproductive tissues. For example, it positively affects body composition by increasing nitrogen retention, which supports lean body mass, muscle size and strength. It also acts on bone to stimulate bone formation.
Testosterone deficiency can result from disease or genetic disorders and is also frequently a complication of aging. Some of the sequelae of adult testosterone deficiency include a wide variety of symptoms including: loss of libido, erectile dysfunction, oligospermia or azoospermia, absence or regression of secondary sexual characteristics, progressive decrease in muscle mass, fatigue, depressed mood and increased risk of osteoporosis.
Several forms of testosterone therapy exist in the United States today. Recently, transdermal preparations have gained favor in the market. However, a scrotal testosterone patch results in supraphysiologic levels of 5α-dihydrotestosterone (DHT) due to the high concentration of 5α-reductase in scrotal skin. It is not known whether these elevated DHT levels have any long-term health consequences. Nonscrotal systems are considered more convenient and most patients achieve average serum concentrations within the normal range and have normal levels of DHT. Oral testosterone therapy is not recommended because doses required for replacement therapy are associated with significant risk of hepatotoxicity.
Testosterone therapy is beneficial in HIV-infected men with a loss of muscle mass. Testosterone therapy has positive effects on the fat-free muscle mass, bone, memory, libido and sense of well-being in HIV-infected men. However, high amounts of testosterone increase the risk of cardiovascular disease and benign prostate hyperplasia (BPH). Although testosterone therapy is able to inhibit wasting in HIV-infected men, it has not been shown to beneficially alter CD4+ levels or viral load.
c. Clomiphene
Clomiphene, which is an antiestrogen related to tamoxifen, has also been used to treat men with low testosterone levels. Clomiphene blocks the normal estrogen feedback on the hypothalamus and subsequent negative feedback on the pituitary. This leads to increases in luteinizing hormone (LH) and follicle stimulating hormone (FSH). In men, these increased levels of gonadotropins stimulate the Leydig cells of the testes and result in the production of higher testosterone levels.
Tenover et al., J. Clin. Endocrinol. Metab. 64:1103, (1987) and Tenover et al., J. Clin. Endocrinol. Metab. 64:1118 (1987) found increased in FSH, LH in both young and old men after treatment with clomiphene. They also found increases in free and total testosterone in men with young men showing significant increases.
Studies were also conducted to determine whether or not clomiphene could be used to improve fertility in men by improving semen quality. Homonnai et al. Fertil. and Steril 50:801 (1988) saw increases in sperm concentration and count but others have not. (See e.g., Sokel, et al., Fertil. and Steril. 49:865 (1988); Check, et al., Int. J. Fertil. 34:120 (1989); Purvis, et al., Int. J. Androl 21:109 (1989); and Breznik, Arch. Androl. 21:109 (1993).) One group saw a deterioration in the percentage of normal sperm with long-term treatment. Shamis, et al., Arch. Androl 21:109 (1991). A WHO study showed no changes in semen quality or fertility after 6 months of treatment. (Androl. 15:299 (1992).) A meta-analysis seems to confirm that testosterone levels go up in men with poor quality sperm but not fertility. (Vanderkerckhove, et al., 2000).
Vandekerckhove, et al. (Cochrane Database Syst Rev 2000;(2):CD000151 (2000)) noted that ten studies involving 738 men have suggested that anti-estrogens appear to have a beneficial effect on endocrinal outcomes, i.e. testosterone, but there is not enough evidence to evaluate fertility effects. Nevertheless should clomiphene administration enhance testosterone levels then one could easily conclude that the drug should positively impact the side effects of testosterone deprivation as long as the testes still retain the ability to respond to gonadotropin stimulation.
Ernst et al., J. Pharmaceut. Sci. 65:148 (1976), have shown that clomiphene is a mixture of two geometric isomers which they refer to as cis,-Z-, clomiphene (cis-clomiphene or zuclomiphene) and trans-,E-, clomiphene, (trans-clomiphene or enclomiphene). According to Ernst, et al. Trans-clomiphene HCl has a melting point of 149° C.–150.5° C., while cis-clomiphene HCI has a melting point of 156.5° C.–158° C. Ernst et al. have also noted that (the trans-isomer) is antiestrogenic (AE) while the cis-isomer is the more potent and more estrogenic form and has also been reported to have anti-estrogenic activity. The authors attribute the effect of the drug on ovulatory activity to both forms stating that the mixture is more effective than trans-clomiphene alone. The trans-isomer aids ovulation at the level of the hypothalamus. The estrogenic isomer cis-clomiphene contributes to enhanced ovulation elsewhere in the physiologic pathway leading to ovulation. The isomers are also reported to have different in vivo half-life. Furthermore the cis form has been reported to leave residual blood levels for in excess of one month following a single dose.
Clomiphene is currently approved as a mixture of both cis- and trans-isomers, the cis-isomer being present as about 30% to 50% (Merck Manual) for fertility enhancement in the anovulatory patient. Clomiphene improves ovulation by initiating a series of endocrine events culminating in a preovulatory gonadotropin surge and subsequent follicular rupture. The drug is recommended to be administered for 5 days at a dose of up to 100 mg daily. Clomiphene has also been associated with numerous side effects including: blurred vision, abdominal discomfort, gynecomastia, testicular tumors, vasomotor flushes, nausea, and headaches. Furthermore, other studies suggest that clomiphene possesses both genotoxic and tumor enhancement effects. The net outcome of these observations is that clomiphene in its current format, having between 30% and 50% of the cis isomer, would be unacceptable for chronic therapy in men.
There continues to be a need for methods of treating wasting in HIV-infected patients. The present invention addresses this need and provides novel compositions and methods for treating wasting in HIV-infected patients.